Neuropeptide Y (hereinafter referred to as “NPY”), a peptide consisting of 36 amino acids, was first isolated from the porcine brain by Tatemoto et al in 1982. (Nature, vol. 296, pp. 659 (1982)). NPY is widely distributed in the central and peripheral nervous systems, and performs diverse functions in vivo as one of the most abundant peptides in the nervous system. That is, NPY acts as an orexigenic substance in the central nervous system, and also promotes markedly the fat-accumulation as mediated by the secretion of various hormones and the action of the nervous systems. Continuous intracerebroventricular administration of NPY is known to induce obesity and insulin resistance on the basis of such actions. (International Journal of Obesity, vol. 19, pp. 517 (1995); Endocrinology, vol. 133, pp. 1753 (1993)). It is also known that NPY has central actions, such as depression, anxiety, schizophrenia, pain, dementia and circadian rhythm control, etc (Drugs, vol. 52, pp. 371 (1996); The Journal of Neuroscience, vol. 18, pp. 3014 (1998)). Furthermore, NPY coexists with norepinephrine at the sympathetic nerve terminals in the peripheral nervous system, and is implicated in the tonicity of the sympathetic nerve system. Peripheral administration of NPY is known to cause vasoconstriction and also to reinforce the actions of other vasoconstrictive substances including norepinephrine (British journal of Pharmacology, vol. 95, pp. 419 (1988)). In addition, NPY is also reported to enhance cardiac hypertrophy as a result of the sympathetic stimulation. (Proceedings of the National Academy of Sciences of the United States of America, vol. 97, pp. 1595 (2000)).
Besides, the said peptide is also reported to be involved in the ability to secrete the sex and growth hormones, sexual and reproductive functions, gastro-intestinal motility, bronchoconstriction, inflammation and alcohol preference (Life Sciences, vol. 55, pp. 551 (1994); The Journal of Allergy and Clinical Immunology, vol. 101, pp. S345 (1998); Nature, vol. 396, pp. 366 (1998)).
NPY exhibits diverse pharmacologic activities via the receptors partially shared by its homologues of the peptide YY and pancreatic polypeptide. These pharmacologic activities of NPY are known to be developed by virtue of at least five types of the receptors either solely or through their mutual interactions. (Trends in Neurosciences, vol. 20, pp. 294 (1997)).
It is reported that the central effects mediated by NPY Y1 receptor include remarkable orexigenic effect (Endocrinology, vol. 137, pp. 3177 (1996)); Endocrinology, vol. 141, pp. 1011 (2000));
NPY can develop its functions through binding to the NPY receptors existing in the central nervous system or the peripheral nervous system. Consequently, inhibition of the binding of NPY to the NPY receptor can prevent NPY from developing its actions. In consequence of this, a substance which acts to antagonize the binding of NPY to the NPY receptor can be expected to be useful in the prophylaxis or treatment of various diseases related to NPY, which diseases are exemplified by the cardiovascular disorders, such as angina, acute or congestive heart failure, myocardial infarction, hypertension, nephropathy, electrolyte abnormality and vasospasm, etc.; diseases of the central nervous system, such as bulimia, depression, anxiety, seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal, circadian rhythm disorders, schizophrenia, memory impairment, sleep disorders, and cognitive impairment, etc.; metabolic diseases, such as obesity, diabetes, hormone abnormality, gout, and fatty liver, etc.; genital or reproductive disorders, such as infertility, preterm labor and sexual dysfunction; gastro-intestinal disorders; respiratory disorders; inflammatory diseases; or glaucoma; and the like (Trends in Pharmacological Sciences, vol. 15, pp. 153 (1994); Life Sciences, vol. 55, pp. 551 (1994); Drugs, vol. 52, pp. 371 (1996); The Journal of Allergy and Clinical Immunology, vol. 101, pp. S345 (1998); Nature, vol. 396, pp. 366 (1998); The Journal of Pharmacology and Experimental Therapeutics, vol. 284, pp. 633 (1998); Trends in Pharmacological Sciences, vol. 20, pp. 104 (1999); Proceedings of the National Academy of Sciences of the United States of America, vol. 97, pp. 1595 (2000); The Journal of Neuroscience, vol. 21, pp. 5367 (2001); Pharmacology & Therapeutics, vol. 65, pp. 397 (1995); Endocrinology, vol. 140, pp. 4046 (1999); American Journal of Physiology, vol. 280, pp. R1061 (2001); American Journal of Physiology, vol. 278, pp. R1627 (2000); Current Opinion in Clinical Nutrition and Metabolic Care, vol. 2, pp. 425 (1999); Current Rheumatology Reports, vol. 3, pp. 101 (2001); American Journal of Respiratory and Critical Care Medicine, vol. 165, pp. 1217 (2002)).
In recent years, the present inventors, after their research and investigation, found additionally that certain NPY receptor antagonists are useful in the prophylaxis or treatment of hypercholesteroleamia, hyperlipidemia and arteriosclerosis (refer to the pamphlet of International Patent Application Publication No. 99/27965).
In the pamphlet of International Patent Application Publication No. 01/46189 (Patent Literature No. 1), there are disclosed a variety of benzimidazole derivatives. However, the said literature does neither disclose nor suggest anything about the antagonistic actions against the NPY receptor of the said derivatives and the compounds of the present invention themselves.
Patent Literature No. 1:
The pamphlet of International Patent Application Publication No. WO 01/46189